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. 2024 Feb 29;89(6):3875–3882. doi: 10.1021/acs.joc.3c02723

Stereoselective Amine Synthesis Mediated by a Zirconocene Hydride to Accelerate a Drug Discovery Program

Athenea N Aloiau 1, Briana M Bobek 1, Kersti Caddell Haatveit 1, Kelly E Pearson 1, Ashlee H Watkins 1, Benjamin Jones 1, Christopher R Smith 1, John M Ketcham 1, Matthew A Marx 1, Stephen J Harwood 1,*
PMCID: PMC10949245  PMID: 38422508

Abstract

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Chiral amine synthesis remains a significant challenge in accelerating the design cycle of drug discovery programs. A zirconium hydride, due to its high oxophilicity and lower reactivity, gave highly chemo- and stereoselective reductions of sulfinyl ketimines. The development of this zirconocene-mediated reduction helped to accelerate our drug discovery efforts and is applicable to several motifs commonly used in medicinal chemistry. Computational investigation supported a cyclic half-chair transition state to rationalize the high selectivity in benzyl systems.

Introduction

Chiral amines are foundational for biology in the form of amino acids.1 Chiral amines also frequently appear as motifs in alkaloid natural products,2 ligands for asymmetric catalysis,3 and in the structures of synthetically derived active pharmaceutical ingredients (APIs).4 The chiral benzylamine is a particularly common element in approved and clinical therapeutic agents (Figure 1A). In 2022 alone, two (olutasidenib5 and mavacamten6) of the 20 small molecules approved by the FDA contained a chiral benzylic amine,7 and this motif is found in some of the highest-revenue marketed drugs, such as cinacalcet.8

Figure 1.

Figure 1

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(A) Selected benzyl amine-containing examples of FDA-approved pharmaceuticals and MRTX0902, a molecule under clinical evaluation. (B) Methodological aspirations for a robust, functional group-tolerant, and stereoselective synthesis of chiral benzyl amine fragments to expedite discovery efforts.

The synthesis of chiral amines remains an active area of synthetic exploration and development due to their ubiquity in biologically active molecules.9 In our own research to develop novel therapies targeting oncogenic drivers of cancer, we have encountered pharmacophores that include a chiral benzylamine element.10 Recently, we developed MRTX0902, a potent, selective, and metabolically stable clinical-stage inhibitor11 of the Son of Sevenless 1 (SOS1): KRAS protein–protein interaction (PPI).12 It is hypothesized that blocking this PPI will increase the available concentration of GDP-bound KRAS protein for selective switch-II KRAS binders to inhibit, thereby potentially increasing the effectiveness of pharmaceutical agents such as adagrasib and sotorasib, which covalently bind KRASG12C in the GDP-bound state.13 During the design and discovery of MRTX0902, currently in phase 1 studies, the benzylamine motif proved to be a critical structural element. Seeking to quickly identify molecules with optimal drug-like properties (1), we desired a practical method to synthesize chiral benzylamines (2, Figure 1B) starting from available or easily synthesized ketones (3). To accelerate our drug discovery efforts, we required a reaction that would provide high stereoselectivity and tolerate many of the common functional groups and heterocycles encountered in a drug discovery program.14 An added benefit would be to develop an operationally safe, simple, and reliable method to conduct.

Chiral sulfinamides are commercially available in either enantiomer, and robust literature precedent exists for their reactivity and selectivity under a variety of reaction conditions. For these reasons, the diastereoselective reduction of chiral sulfinyl ketimines appeared to be a practical foundation to develop our chemistry platform (Figure 2A).15 In particular, tert-butanesulfinamide (4), known as Ellman’s sulfinamide,16 undergoes condensation easily onto ketones in the presence of a Lewis acid and desiccant, such as titanium(IV) ethoxide, at elevated temperatures to provide ketimines chiral at sulfur (5).16,17 Upon exposure of the ketimine to a coordinating metal hydride such as sodium borohydride, borane, DIBAL-H, or lithium aluminum hydride, Andersen et al. have proposed that these reductions occur through a closed, six-membered chairlike transition state where the larger α-substituent of the imine and the tert-butyl group on sulfur are placed in equatorial positions (Figure 2B).18 For poorly coordinating hydride reductants such as L-selectride and lithium triethylborane (superhydride), an open transition state is proposed for the reduction where diastereoselectivity is determined by the approach of the hydride from the same face as the lone pair on sulfur, away from the bulky substituents of the auxiliary (Figure 2B). The auxiliary group of the resulting tert-butyl sulfinamide product (6) can be removed under mildly acidic or oxidative conditions to reveal the desired chiral amine. Frequently, these reductions require careful chromatographic purification to separate the resulting diastereomers, thereby providing amines of suitable enantiopurities for drug discovery programs after auxiliary removal.

Figure 2.

Figure 2

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(A) Traditional approaches to the synthesis and diastereoselective reduction of sulfinyl ketimines. (B) Commonly invoked stereochemical models explain diastereoselective outcomes. (C) Efforts to identify a reductant of suitable diastereo- and chemoselectivity for our drug discovery program. aCombined NMR yield. bIsolated yield.

Results and Discussion

To obtain meaningful selectivity in the reduction, these reactions are typically run at cryogenic temperatures (often −78 °C) for as long as 16 h.15c These reactions and reagents are moisture-sensitive, which requires a careful reaction setup to avoid adventitious water. Many common functional groups, particularly electrophiles and electron-deficient heterocycles, do not survive these strongly reducing conditions. In our program to develop a SOS1: KRAS PPI inhibitor, we encountered these challenges using conventional reaction conditions (Figure 2C). In exploring the reduction of chiral sulfinyl ketimine (7) bearing an electrophilic nitrile and sterically encumbering ortho-methyl group, we found that small, mild reductants (sodium borohydride) gave poor diastereoselectivity, and larger, strong reductants (DIBAL-H, superhydride) gave better selectivity, albeit with lower yields. The more conventional reductant, L-selectride, appeared to give the best combination of selectivity and yield (83% yield, 1:10.5 dr). Seeking a more practical solution, we took inspiration from an example using Zirconocene chloride hydride (Schwartz’s reagent, initially reported by Wailes and Weigold)19 reported by scientists at Sepracor Inc. (now Sunovion Pharmaceuticals Inc.) in a provisional patent application demonstrating a highly diastereoselective reduction of an alkyl sulfinyl ketimine at −20 °C in tetrahydrofuran.20 Additionally, a report by Šebesta and co-workers demonstrating the reduction of sulfonyl imines using Schwartz’s reagent in dichloromethane at room temperature provided additional support that this reactivity could be possible.21 Gratifyingly, we found that the use of this highly oxophilic zirconium hydride (1.1 equiv) in the noncoordinating solvent dichloromethane provided a 77% isolated yield of our desired sulfinamide diastereomer 8 in >20:1 selectivity after just 1 hour at room temperature under an ambient atmosphere.

Having identified convenient diastereo- and chemoselective22 reaction conditions, we next applied this reaction system to enable the synthesis of benzylamines relevant to our drug discovery campaign (Figure 3). Functional groups in the ortho-, meta-, and para-positions were all well-tolerated (9–15). Aryl halides, critical functionality in medicinal chemistry,23 survive the zirconium hydride reduction (13–16). Protic functional groups such as sulfonamide (17),24 anilines (18, 19), and even phenol (20) do not impact the selectivity of the reaction. Electrophilic functional groups such as esters (21) and nitriles (8, 22)25 can be present in the reaction without detriment. In the series: methyl, ethyl, and isopropyl (23–25), selectivity erodes with branching alkyl groups or biaryl systems (26).

Figure 3.

Figure 3

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Application of ketimine reduction using a zirconium hydride in systems relevant to medicinal chemistry. This includes electron-donating and -withdrawing groups, ortho-substituted arenes, protic functionality, activated halopyridines, electron-deficient azines, common azoles, and conjugated imines.

A crucial test for any methodology to be relevant to medicinal chemistry is its ability to perform in the presence of heterocyclic systems. Pyridine substitution at every position is well-tolerated (27–29). Significantly, activated halopyridines survive this reaction without dehalogenation (30, 31). Chiral sulfinamide (32), an intermediate in the synthesis of a partial allosteric modulator of the α-7 nicotinic acetylcholine receptor,26 bears a 2-aminopyridine motif and a pyrazine. Popular pyrimidines (33) and pyridazines (34) are also tolerated under the standard reaction conditions.14a,27 We next turned our attention toward common azoles. Pyrazole (35) and isothiazole (36) were tolerated under the reaction conditions. The N-substituted triazole (37), an unnatural heterocycle frequently used in medicinal chemistry for its synthetic tractability,28 also survived the reduction. The zirconium hydride reduction worked well in the presence of a thiophene and thioether (38),29 albeit with poor diastereoselectivity for this unique 5,6-ring system. Interestingly, oxazole 39 was obtained in a 15:1 diastereomeric ratio compared to the higher selectivity observed with thiazole 40, possibly due to its comparatively smaller size. Lastly, several alkyl and allylic imines were treated under the optimized reaction conditions. The reduction to homobenzylic sulfinyl amide 41 was not sterically differentiated enough to provide selectivity with Schwartz’s reagent; however, chemoselective 1,2-reduction of a conjugated ketimine was obtained with reasonable diastereoselectivity (42). Carbamates such as the one contained in 43 were left untouched under the reaction conditions. In the sterically differentiated case of 44, the selectivity was exquisite, leading to an >20:1 dr. Interestingly, high selectivity was observed in the case of methyl vs adamantyl (45), a notoriously challenging and valuable system previously requiring the use of a noncommercial chiral sulfinamide.30

Two examples highlight the practicality and applicability of this method to real-world drug discovery (Figure 4). The synthesis of MRTX0902, prior to the development of this methodology, utilized a six-step sequence from bromide 46 involving ketimine formation, L-selectride reduction, auxiliary removal, amine protection, palladium-catalyzed cyanation, and deprotection (Figure 4A).12a

Figure 4.

Figure 4

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Case studies demonstrate the ability to accelerate research programs. (A) Concession steps were removed in the synthesis of MRTX0902 with a direct and stereoselective reduction of ketimines bearing nitrile functional groups. (B) High chemoselectivity of Schwartz’s reagent allowed for the reduction of an unprotected indole system, removing concession steps from the synthesis of 50 contained in several PAK1 inhibitor analogues.

Starting with the nitrile 47, we conducted the ketimine formation and zirconium hydride reduction on a gram-scale, followed by auxiliary removal to afford chiral amine 48 in just three steps, obviating protecting groups and shortening the synthesis to the final API. In a second example, several indole-containing P21 (RAC1)-activated kinase 1 (PAK1) inhibitors were reported by Genentech (Figure 4B).31 In their preliminary patent application, starting from ketone 49, a robust seven-step sequence of indole nitrogen protection, ketone reduction, Appel reaction, phthalimide installation, benzylamine deprotection, and indole nitrogen deprotection was utilized to prepare the racemic benzylic amine. Subsequent resolution via chiral supercritical fluid chromatography provided difficult-to-access chiral amine 50. Recognizing that protic functionalities are tolerated in this reduction reaction, we envisioned a reduction of a ketimine derived from the same ketone 49 bearing the unprotected indole nitrogen, which after auxiliary removal provided 50 in just three steps without indole protection.

To elucidate the origin of diastereoselectivity, density functional theory (DFT) was used to compute several proposed transition-state models performed at the M06-2X-D3/6-311+G(d,p)/LANL2DZ(Zr)//B3LYP/6-31G(d)/LANL2DZ (Zr) level of theory using ketimine 23 as a representative system for the aryl methyl motif of most substrates. Several variations of the published proposed closed and open transition states for tetracoordinated and pentacoordinated zirconocene complexes were calculated. The tetracoordinate complex was derived from an X-type ligand substitution of the chloride for the sulfinyl oxygen. A four-membered transition state involving imine coordination was also calculated, inspired by a reported zirconocene proposal21 (for a full discussion of explored transition states and results, see Supporting Information, Figures S1–S5). The transition-state model was narrowed down to the closed six-membered ring transition states containing a tetrahedral zirconocene (TS-1a,b) as the alternative models showed inverse diastereoselectivity in preference for the not observed (RS, S)-product ((S)-23, Figure 5A). An associative mechanism for X-type ligand substitution was computed, and the energy barriers for this substitution were reasonable (ΔG⧧ of 5.6 and 20.8 kcal/mol for each step), supporting this transition state as a viable model (Figure S1).

Figure 5.

Figure 5

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DFT computations of the diastereoselectivity model for the reduction of sulfinyl imines via the Schwartz reagent. (A) Lowest energy RS, R and RS, S transition states as half-chairs for model system 23. (B) Lowest energy RS, R and RS, S transition states as half-chairs for the ethyl methyl model system for 41 demonstrate minimal diastereoselectivity.

Interestingly, the model proposed by Andersen et al. is a chair;18 however, in the zirconocene complex, the lowest energy transition states are optimized to half-chairs due to geometric constraints on the system. These constraints include the proximity of the large cyclopentadienyl ligand to the pseudoaxial substituent and the requirement of a nearly linear angle for hydride transfer in the transition state. This creates a C–H–Zr–O dihedral angle close to 0°. The lowest energy transition state TS-1a (leading to the experimentally observed RS, R product) has the phenyl substituent in the pseudoequatorial position, whereas TS-1b (leading to the RS, S product) has the methyl substituent placed pseudoequatorially. The alternative half-chair patterns which place the tert-butyl group of the auxiliary pseudoaxial are higher in energy, resulting from the 1,3-diaxial steric clash of the tert-butyl and pseudoaxial groups of the ketimine substrate (Figure S2).

Comparing the energies of the two most reasonable tetracoordinated half-chair transition states (TS-1a and TS-1b), the ΔΔG⧧ is 1.5 kcal/mol. This aligns well with the experimental results demonstrating mostly >20:1 dr for substrates containing an aromatic methyl imine (Figure 5A). The difference in energy between these two transition states is due to a minimized steric clash between a cyclopentadienyl ligand and the phenyl group. With the phenyl in the pseudoequatorial position, the distance between the two groups is 3.0 Å compared to 2.8 Å when the phenyl is pseudoaxial. For further validation, a truncated model of 41 (which showed minimal experimentally observed diastereoselectivity) was computed. An insignificant energy difference with a ΔΔG⧧ of −0.3 kcal/mol was observed computationally—matching experimental observations (Figure 5B). This is easily rationalized given that ethyl and methyl substituents are similar in size; therefore, only minimal differences in steric interactions between pseudoequatorial and pseudoaxial positions result. Similarly, computing the phenyl iso-propyl ketimine 25, which demonstrated only slight diastereoselectivity experimentally, has two relatively large substituents compared to 41 containing two relatively small substituents. In this case, there was also no significant energy difference with a ΔΔG⧧ of −0.1 kcal/mol. It can be concluded that the diastereoselectivity in this system is driven by the relative difference in size between the substituents of the sulfinyl ketimine. While these results suggest a half-chair transition state with the largest groups placed pseudoequatorial, the chair transition state with the largest groups placed equatorial still serves as a useful model for predicting the stereoselective outcome for this zirconocene hydride reduction.

Conclusions

In summary, to accelerate analog synthesis, Schwartz’s reagent was developed as a mild and diastereoselective reductant for the chiral synthesis of benzylamines. This reaction proved to be operationally simple and tolerant to moisture and air. Many functional groups and heterocyclic systems frequently used in medicinal chemistry were well-tolerated under the reaction conditions, and several examples from the pharmaceutical literature were selected as case studies. Two examples particularly highlighted how sulfinyl ketimine reduction with a zirconium hydride can accelerate discovery efforts and shorten synthetic sequences. Computational investigation using DFT suggested that this reduction is occurring through a half-chair transition state after associative ligand exchange. The unusually high stereoselectivity of this reduction is postulated to result from zirconium’s high oxophilicity driving substrate coordination and the minimization of steric clashes between the cyclopentadienyl ligand and the aryl ring of the substrate in the half-chair transition state. Efforts are underway to further improve the stereoselectivity of this transformation and render it catalytic.

Experimental Section

General Procedure A: Ketimine Formation

graphic file with name jo3c02723_0006.jpgTo a solution of ketone (1.0 equiv) and (R)-2-methylpropane-2-sulfinamide (1.2 equiv) in anhydrous tetrahydrofuran was added titanium(IV) ethoxide (5.0 equiv) in a sealed vial. The sealed vial was placed in a heating block at 80 °C for the specified time and then cooled to room temperature. Once at room temperature, the reaction was diluted with ethyl acetate, and with stirring, a minimal amount of brine was added to form a suspension. The resulting suspension was filtered through a pad of Celite, and the filter cake was washed with ethyl acetate several times. The filtrate was concentrated under reduced pressure to provide the crude product, which was purified via silica gel chromatography to provide the pure sulfinyl ketimine.

General Procedure B: Reduction of Sulfinyl Ketimine

graphic file with name jo3c02723_0007.jpgTo a solution of sulfinyl imine (0.500 mmol) in dichloromethane (3.33 mL, 0.15 M) at room temperature in a vial was added Schwartz’s reagent (142 mg, 1.10 equiv, 0.550 mmol) as a solid portionwise (note: a minimal amount of bubbling was observed, possibly hydrogen). The reaction was stirred at this temperature for 1 h before being quenched with aqueous ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organics were washed successively with water twice, then brine. The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. This residue was purified via silica gel chromatography to provide the sulfinamide.

Acknowledgments

The authors would like to thank the Mirati drug discovery and chemical process research and development teams for thoughtful discussion and support. In particular, Todd Baumgartner, for his tremendous assistance with analytical support. The authors are grateful to OpenEye for their cloud computing resources and support with the Gaussian module for the calculations. All research described in this manuscript was funded by Mirati Therapeutics.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.3c02723.

  • Synthetic experimental procedures, characterization, and spectral data for compounds 7–50; computational experimental procedures; DFT basis sets; discussion; mechanism and free energy profile of ligand substitution; all tetracoordinated closed transition-state models for ketimine S23, ketimine S41, and ketimine S25; and DFT calculations (PDF)

Author Contributions

A.N.A. and B.M.B. contributed equally. J.M.K. and S.J.H.: conceptualization. A.N.A., A.H.W., B.M.B., K.C.H., K.E.P., B.J., and S.J.H.: methodology, investigation, and formal analysis. K.C.H.: software. C.R.S., J.M.K., K.C.H., M.A.M., and S.J.H.: writing, review, and visualization. All authors have given approval to the final version of the manuscript.

The authors declare the following competing financial interest(s): All authors are employees of Mirati Therapeutics.

Supplementary Material

jo3c02723_si_001.pdf (11.7MB, pdf)

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Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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